Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>

ABSTRACT Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated th...

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Autores principales:	Andrew S. Herbert, Cristin Davidson, Ana I. Kuehne, Russell Bakken, Stephen Z. Braigen, Kathryn E. Gunn, Sean P. Whelan, Thijn R. Brummelkamp, Nancy A. Twenhafel, Kartik Chandran, Steven U. Walkley, John M. Dye
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/263ccfc6711f4321bc9f6e259ae2e4fb
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spelling	oai:doaj.org-article:263ccfc6711f4321bc9f6e259ae2e4fb2021-11-15T15:49:02ZNiemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>10.1128/mBio.00565-152150-7511https://doaj.org/article/263ccfc6711f4321bc9f6e259ae2e4fb2015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00565-15https://doaj.org/toc/2150-7511ABSTRACT Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated the importance of NPC1, and its partner in cholesterol transport, NPC2, by using a mouse model of Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads and succumbed to EBOV infection, Npc1−/− mice were entirely free of viral replication and completely protected from EBOV disease. Interestingly, Npc1+/− mice transiently developed high levels of viremia, but were nevertheless substantially protected from EBOV challenge. We also found Npc2−/− mice to be fully susceptible to EBOV infection, while Npc1−/− mice treated to deplete stored lysosomal cholesterol remained completely resistant to EBOV infection. These results provide mechanistic evidence that NPC1 is directly required for EBOV infection in vivo, with little or no role for NPC1/NPC2-dependent cholesterol transport. Finally, we assessed the in vivo antiviral efficacies of three compounds known to inhibit NPC1 function or NPC1-glycoprotein binding in vitro. Two compounds reduced viral titers in vivo and provided a modest, albeit not statistically significant, degree of protection. Taken together, our results show that NPC1 is critical for replication and pathogenesis in animals and is a bona fide target for development of antifilovirus therapeutics. Additionally, our findings with Npc1+/− mice raise the possibility that individuals heterozygous for NPC1 may have a survival advantage in the face of EBOV infection. IMPORTANCE Researchers have been searching for an essential filovirus receptor for decades, and numerous candidate receptors have been proposed. However, none of the proposed candidate receptors has proven essential in all in vitro scenarios, nor have they proven essential when evaluated using animal models. In this report, we provide the first example of a knockout mouse that is completely refractory to EBOV infection, replication, and disease. The findings detailed here provide the first critical in vivo data illustrating the absolute requirement of NPC1 for filovirus infection in mice. Our work establishes NPC1 as a legitimate target for the development of anti-EBOV therapeutics. However, the limited success of available NPC1 inhibitors to protect mice from EBOV challenge highlights the need for new molecules or approaches to target NPC1 in vivo.Andrew S. HerbertCristin DavidsonAna I. KuehneRussell BakkenStephen Z. BraigenKathryn E. GunnSean P. WhelanThijn R. BrummelkampNancy A. TwenhafelKartik ChandranSteven U. WalkleyJohn M. DyeAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Andrew S. Herbert Cristin Davidson Ana I. Kuehne Russell Bakken Stephen Z. Braigen Kathryn E. Gunn Sean P. Whelan Thijn R. Brummelkamp Nancy A. Twenhafel Kartik Chandran Steven U. Walkley John M. Dye Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
description	ABSTRACT Recent work demonstrated that the Niemann-Pick C1 (NPC1) protein is an essential entry receptor for filoviruses. While previous studies focused on filovirus entry requirements of NPC1 in vitro, its roles in filovirus replication and pathogenesis in vivo remain unclear. Here, we evaluated the importance of NPC1, and its partner in cholesterol transport, NPC2, by using a mouse model of Ebolavirus (EBOV) disease. We found that, whereas wild-type mice had high viral loads and succumbed to EBOV infection, Npc1−/− mice were entirely free of viral replication and completely protected from EBOV disease. Interestingly, Npc1+/− mice transiently developed high levels of viremia, but were nevertheless substantially protected from EBOV challenge. We also found Npc2−/− mice to be fully susceptible to EBOV infection, while Npc1−/− mice treated to deplete stored lysosomal cholesterol remained completely resistant to EBOV infection. These results provide mechanistic evidence that NPC1 is directly required for EBOV infection in vivo, with little or no role for NPC1/NPC2-dependent cholesterol transport. Finally, we assessed the in vivo antiviral efficacies of three compounds known to inhibit NPC1 function or NPC1-glycoprotein binding in vitro. Two compounds reduced viral titers in vivo and provided a modest, albeit not statistically significant, degree of protection. Taken together, our results show that NPC1 is critical for replication and pathogenesis in animals and is a bona fide target for development of antifilovirus therapeutics. Additionally, our findings with Npc1+/− mice raise the possibility that individuals heterozygous for NPC1 may have a survival advantage in the face of EBOV infection. IMPORTANCE Researchers have been searching for an essential filovirus receptor for decades, and numerous candidate receptors have been proposed. However, none of the proposed candidate receptors has proven essential in all in vitro scenarios, nor have they proven essential when evaluated using animal models. In this report, we provide the first example of a knockout mouse that is completely refractory to EBOV infection, replication, and disease. The findings detailed here provide the first critical in vivo data illustrating the absolute requirement of NPC1 for filovirus infection in mice. Our work establishes NPC1 as a legitimate target for the development of anti-EBOV therapeutics. However, the limited success of available NPC1 inhibitors to protect mice from EBOV challenge highlights the need for new molecules or approaches to target NPC1 in vivo.
format	article
author	Andrew S. Herbert Cristin Davidson Ana I. Kuehne Russell Bakken Stephen Z. Braigen Kathryn E. Gunn Sean P. Whelan Thijn R. Brummelkamp Nancy A. Twenhafel Kartik Chandran Steven U. Walkley John M. Dye
author_facet	Andrew S. Herbert Cristin Davidson Ana I. Kuehne Russell Bakken Stephen Z. Braigen Kathryn E. Gunn Sean P. Whelan Thijn R. Brummelkamp Nancy A. Twenhafel Kartik Chandran Steven U. Walkley John M. Dye
author_sort	Andrew S. Herbert
title	Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
title_short	Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
title_full	Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
title_fullStr	Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
title_full_unstemmed	Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>
title_sort	niemann-pick c1 is essential for ebolavirus replication and pathogenesis <italic toggle="yes">in vivo</italic>
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/263ccfc6711f4321bc9f6e259ae2e4fb
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Niemann-Pick C1 Is Essential for Ebolavirus Replication and Pathogenesis <italic toggle="yes">In Vivo</italic>

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